The invention pertains to novel substituted heterocyclic aminopyrrolidine derivatives having drug and bio-affecting properties and to their preparation, pharmaceutical formulations and use. In particular, the invention concerns benzodioxoles, benzofurans, dihydrobenzofurans, dihydrobenzodioxanes and related derivatives bearing substituted aminopyrrolidine groups. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. Melatonin levels show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. ##STR2##
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125 I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the CNS of a variety of species. The sequences of two cloned human melatonin receptors have been reported [Reppert, et al., Proc. Natl. Acad. Sci. 92, p. 8734-8738, (1995) and Reppert, et al., Neuron 13, p. 1177-1185, (1994)]. In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures. Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discreet nuclei of the hypothalamus. In humans, specific [.sup.125 I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487, published on Apr. 14, 1994.
Thus, melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, premenstrual syndrome, immune disorders, inflammatory articular diseases and neuroendocrine disorders.
Aside from simple indole derivatives of melatonin itself, various bicyclic structures have been prepared and their use as melatonin ligands disclosed. In general these bicyclic amide structures can be represented as: ##STR3##
wherein Z is an aryl or heteroaryl system attached by a two carbon bridge to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EP-527,687A, published on February 17, 1993, disclose as melatonin ligands arylethylamines i, ##STR4##
wherein Ar' is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
Yous, et al. in European Patent Application EP-506,539A, published on Sep. 30, 1992, claim ligands ii, ##STR5##
wherein A is oxygen or sulfur; X is a methylene group or a bond; and R is H or lower alkyl when p is 1 and B is defined by the radical iii, ##STR6##
wherein R.sub.1 is hydrogen or lower alkyl and R.sub.2 is, inter alia, hydrogen, lower alkyl or cycloalkyl. Alternatively, R is defined by the radical iii when p is 0 or 1 and B is lower alkoxy.
Several naphthalene derivatives have also been disclosed as melatonin ligands.
Yous, et al. in European Patent Application EP-562,956A, published on Sep. 29, 1993, disclose amide and urea naphthalene derivatives iv, ##STR7##
in which R is hydrogen or OR.sub.4 wherein R.sub.4 is, inter alia, hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R.sub.1 is hydrogen or COOR.sub.5 wherein R.sub.5 is hydrogen or alkyl; R.sub.2 is hydrogen or alkyl; X is NH or a bond; and R.sub.3 is, inter alia, alkyl, alkenyl, or cycloalkyl.
Horn and Dubocovich in European Patent Application EP-420,064A, published on Apr. 3, 1991, disclose 2-amidotetralins v as melatonin ligands, ##STR8##
wherein R.sub.1 is, inter alia, hydrogen, lower alkyl, or lower alkoxyl; R.sub.2 is, inter alia, hydrogen, halogen, or lower alkoxyl; R.sub.3 is, inter alia, hydrogen, or lower alkyl; R.sub.4 is, inter alia, lower alkyl, haloalkyl or cycloalkyl; and R.sub.5 is hydrogen, hydroxyl, halogen, oxo, aryl, lower alkyl or alkylaryl.
Lesieur et al, in EP-708,099A, published Apr. 24, 1996, disclose compounds of structure vi, which are useful for the treatment of diseases caused by a melatonin imbalance. ##STR9##
wherein {character pullout} is a single or double bond; R.sub.1.dbd.Me or MeNH; and X--Y.dbd.--CH(Me)--CH.sub.2 --, CH.sub.2 CH(OH)-- or (CH.sub.2).sub.3 --.
North et al., in International Application WO 95/29173, published Nov. 2, 1995, disclose naphthalene derivatives of structure vii: ##STR10##
wherein R.sub.1 is a group of the formula CR.sub.3 R.sub.4 (CH.sub.2)pNR.sub.5 COR.sub.6 ; R.sub.2 is hydrogen, halogen, C.sub.1-6 alkyl, OR.sub.7 or CO.sub.2 R.sub.7 ; and may be the same or different substituent when q is 2; R.sub.3, R.sub.4 and R.sub.5, which may be the same or different, are hydrogen or C.sub.1-6 alkyl; R.sub.6 is C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; R.sub.7 is hydrogen or C.sub.1-6 alkyl; n is zero, 1 or 2; p is an integer of 1, 2, 3 or 4; q is 1 or 2; and the dotted lines indicate the absence or presence of an additional bond. The North et al. compounds are taught to treat chronobiological disorders.
In International Application WO 95/17405, published on Jun. 29, 1995, North et al., disclose compounds of structure viii and teach their use in the treatment of conditions related to the melatonin system. ##STR11##
wherein R.sub.1 is hydrogen, halogen or C.sub.1-6 alkyl; R.sub.2 is a group of formula --CR.sub.3 R.sub.4 (CH.sub.2).sub.p NR.sub.5 COR.sub.6 ; R.sub.3, R.sub.4 and R.sub.5, which may be the same or different, are hydrogen or C.sub.1-6 alkyl; R.sub.6 is C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; n is an integer of 2, 3 or 4; and p is an integer of 1, 2, 3 or 4.
Keavy, et al., in U.S. Pat. No. 5,753,709, issued on May 19, 1998, disclose compounds of formula ix which are useful as melatonergic agents, ##STR12##
wherein X represents halogen, hydrogen, C.sub.1-4 alkyl or OR.sub.5 wherein, inter alia, R.sub.5 is hydrogen, C.sub.1-20 alkyl or C.sub.4-20 alkylcycloalkyl; Y represents hydrogen or halogen; X represents inter alia, hydrogen, halogen, cyano or aryl; R represents hydrogen, halogen or C.sub.1-4 alkyl or; R.sub.1 represents hydrogen, C.sub.1-4 alkyl or benzyl and R.sub.2 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.2-4 alkoxyalkyl, C.sub.1-4 trifluoromethylalkyl or C.sub.2-8 alkylthioalkyl.
In International Application WO 97/43272, published on Nov. 20, 1997, Ellis, et al., disclose compounds of structure x as melatonin ligands. ##STR13##
wherein R.sup.1 and R.sup.2 represent hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl or aryl, R.sup.3 and R.sup.4 represent hydrogen, halogen or C.sub.1-6 alkyl or substituted aryl, R.sup.5 represents hydrogen or C.sub.1-6 alkyl, n is 0-2, m is 1-4 and the dotted line represents an additional bond.
Catt, et al., in U.S. Pat. No. 5,856,529, issued on Jan. 5, 1999, disclose compounds of formula xi which are useful as melatonergic agents, ##STR14##
wherein Q.sup.1 and Q.sup.2 represent hydrogen or halogen; X represents CH.sub.2, CH or oxygen; Y represents CR.sup.3, CR.sup.3 R.sup.4 or (CH.sub.2).sub.n with n=1-4; Z represents CH.sub.2, CH or oxygen; R represents hydrogen, halogen or C.sub.1-4 alkyl; m is 1 or 2; R.sup.2 represents hydrogen or C: .sub.4 alkyl and R.sup.1 represents C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-3 haloalkyl, C.sub.1-6 alkylamino, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy(C.sub.1-4)alkyl, C.sub.1-4 alkylthio(C.sub.1-4)alkyl or C.sub.1-4 trifluoromethylalkyl.
The foregoing disclosures do not teach or suggest the novel melatonergic heterocyclic aminopyrrolidine derivatives of the present invention. The novel compounds of the present invention display melatonergic agonist activity.